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Summary sheet: Codeine
Chemical Nomenclature
Common names Codeine
Substitutive name 3-methylmorphine
Systematic name (5α,6α)-7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
Class Membership
Psychoactive class Opioid
Chemical class Morphinan
Routes of Administration


Threshold 30 mg
Light 50 - 100 mg
Common 100 - 150 mg
Strong 150 - 200 mg
Heavy 200 mg +
Total 3 - 6 hours
Onset 30 - 45 minutes



Codeine (also known as 3-Methylmorphine) is a naturally-occurring opioid substance of the morphinan class found in extracts of the poppy, particularly Papaver bractreatum.[1] Members of this group produce effects such as sedation, cough suppression, and euphoria when administered.

Codeine is the second most predominant alkaloid in opium (up to three percent).[citation needed] Although codeine can be extracted from natural sources, a semi-synthetic process is the primary source of codeine for pharmaceutical use. It is considered the prototype of the weak to midrange opioids (tramadol, dextropropoxyphene, dihydrocodeine and hydrocodone.[citation needed]

Codeine is currently the most widely used opiate in the world,[2][3] and is one of the most commonly used drugs overall according to numerous reports by organizations including the World Health Organization and its League of Nations predecessor agency. It is one of the most effective orally administered opioid analgesics and has a wide safety margin.

Recreationally, it is usually purchased over the counter within painkillers that mix it with other more toxic substances. These can be separated using a cold water extraction technique.


Codeine, or 3-methylmorphine, is an opioid of the morphinan class. Codeine and other molecules of this class contain a polycyclic core of three benzene rings fused in a zig-zag pattern called phenanthrene. A fourth nitrogen-containing ring is fused to the phenanthrene at R9 and R13 with the nitrogen member looking at R17 of the combined structure. This structure is called morphinan. Codeine (along with other morphinans) contains an ether bridge between two of its rings, connecting R4 and R5 through an oxygen group. It contains a hydroxy group (OH-) bound at R6 and a methyl group located on the nitrogen atom at R17.

On the same ring containing the hydroxy group, codeine contains a double bond which dihydrocodeine lacks. Codeine is closely related to morphine as both contain an oxygen group at R3, but this oxygen group in codeine is substituted by a methyl group (making a methoxy group). Codeine is analogous to the other morphinans including dihydrocodeine, heroin, ethylmorphine, hydrocodone, and oxycodone.


Codeine is not itself centrally active, and must first be converted via first-pass metabolism into morphine by the cytochrome P450 enzyme CYP2D6 (as such, it is a prodrug for morphine). Codeine is also metabolized into the inactive norcodeine via the CYP3A4 enzyme system. Both resultant forms are conjugated by UGT2B7 into their corresponding 3-glucuronide.[citation needed]

Some percentage of the population produces less CYP2D6 enzymes and so experience a significant reduction of effects from codeine in comparison to that of the average person. However, others produce CYP2D6 enzymes in higher quantities which can result in hypersensitivity to the drug. Some methods of potentiating opioids, such as using grapefruit juice throughout the day before consumption, inhibits the CYP3A4 enzyme.[4] This results in less codeine being converted into norcodeine which leaves more to be metabolized into morphine. This also indicates a lacking capability in the metabolism of codeine into morphine when a user consumes antihistamines such as diphenhydramine prior to the ingestion of codeine. [5]

There is an upper limit to the amount of codeine which can be converted by enzymatic metabolism into morphine throughout an individual session. This limit is commonly referred to as the "ceiling dose", which is commonly believed to be around 400mg. Consuming higher doses will lead to greater side effects such as itchiness and nausea, but will not increase euphoria.

The active metabolites of codeine, notably morphine, exert their effects by binding to and activating opioid receptors, mainly the μ-opioid receptor.[6] This occurs because opioids structurally mimic endogenous endorphins which are naturally found within the body and also work upon the μ-opioid receptor set. The way in which opioids structurally mimic these natural endorphins results in their euphoria, pain relief, muscle relaxing and anxiolytic effects. This is because endorphins are responsible for reducing pain, causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or general excitement.

Codeine itself is a weak ligand for the opioid receptors. However, its main active metabolite, morphine, shows much stronger agonistic effects.

Binding affinities (Ki)[7]

  • Mu opioid agonist - 589 nM
  • Kappa opioid agonist - 18061 nM
  • Delta opioid agonist - 11442 nM

Subjective effects


Physical effects

Cognitive effects

Visual effects

Experience reports


Common forms

Codeine is available within pharmacies across the world in a variety of forms that combine it with other products that are dangerous or even fatal to consume at higher dosages. This is done to act as a deterrent to prevent their recreational use but can easily be circumvented with the use of a cold water extraction.

Toxicity and harm potential

Codeine has a low toxicity relative to dose. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. Some people may also have an allergic reaction to codeine, such as the swelling of skin and rashes.[8] It is also potentially lethal when mixed with depressants like alcohol or benzodiazepines.


Tolerance and addiction potential

As with other opioids, the chronic use of codeine can be considered moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.

Tolerance to many of the effects of codeine develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Codeine presents cross-tolerance with all other opioids, meaning that after the consumption of codeine all opioids will have a reduced effect.

Dangerous interactions


  • Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Place affected patients in the recovery position to prevent vomit aspiration from excess. Memory blackouts are likely
  • Amphetamines - Stimulants increase respiration rate which allows for a higher dose of opiates than would otherwise be used. If the stimulant wears off first then the opiate may overcome the user and cause respiratory arrest.
  • Benzodiazepines - Central nervous system and/or respiratory-depressant effects may be additively or synergistically present. The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position blackouts/memory loss likely.
  • DXM - CNS depression, difficult breathing, heart issues, hepatoxic, just very unsafe combination all around. Additionally if one takes DXM, their tolerance of opiates goes down slightly, thus causing additional synergistic effects.
  • GHB/GBL - The two substances potentiate each other strongly and unpredictably, very rapidly leading to unconsciousness. While unconscious, vomit aspiration is a risk if not placed in the recovery position
  • Ketamine - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
  • MAOIs - Coadministration of monoamine oxidase inhibitors (MAOIs) with certain opioids has been associated with rare reports of severe and fatal adverse reactions. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases.
  • MXE - This combination can potentiate the effects of the opioid
  • Nitrous - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.
  • PCP - PCP can reduce opioid tolerance, increasing the risk of overdose.
  • Tramadol - Concomitant use of tramadol increases the seizure risk in patients taking other opioids. These agents are often individually epileptogenic and may have additive effects on seizure threshold during coadministration. Central nervous system- and/or respiratory-depressant effects may be additively or synergistically present

Legal status

  • Australia: In Australia, codeine preparations are Schedule 4 (Prescription Only) medications when combined with other substances[9]. Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate linctus) are available on prescription and are considered Schedule 8 (Controlled Drug (Possession without authority illegal))[10]. Schedule 8 drugs are drugs that are available to be prescribed but are heavily restricted to prevent abuse and dependence[11]. Possessing Schedule 8 drugs without authority is a criminal offense and can have varying punishments depending on the state of prosecution.
  • Austria: Codeine is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).[citation needed]
  • Canada: In Canada, codeine is available over the counter in combination tablets with the following restrictions: no more than 8 mg per dosage unit and it must be combined with at least two other active ingredients. It is kept behind the counter, to be sold on request-- generally to those 18 and over-- after a brief consultation and at the pharmacist's discretion. The other active ingredients most commonly consist of another non-opioid analgesic (300 mg acetaminophen, as in Tylenol No. 1; or 325 mg aspirin, as in 222s) and 15 mg caffeine. OTC tablets containing ibuprofen are generally unavailable. Preparations with a codeine content higher than 8 mg per dosage unit, or fewer than two other active ingredients, are available on prescription.[citation needed]
  • Denmark: In Denmark, codeine is sold over the counter with max 9.6 mg in the mixture. The item is given over the counter, with no prescriptions. The strongest available over the counter preparation containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger requires a prescription for legal possession.[citation needed]
  • Finland: In Finland, codeine cough syrups with a maximum strength of 1mg/ml is sold in pharmacies over the counter. Codeine isn't available in pill form without a prescription. Any stronger cough syrup and combination painkillers (codeine with paracetamol or ibuprofen such as Panacod, Co-codamol, and Ardinex) require a prescription.[citation needed]
  • France: In France, most preparations containing codeine do not require a doctor's prescription. Example products containing codeine include Néocodion (cough pills, and syrup), Codoliprane (codeine with paracetamol), Prontalgine and Migralgine (codeine, paracetamol, and caffeine).[12]
  • Germany: Codeine is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form. There is an exception for preparations, containing up to 2,5% or 100mg codeine per unit, which can be prescribed on a regular prescription if not prescripted to an alcohol or drug dependent person.[13]
  • Greece: Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably be arrested, even if they were legitimately prescribed it in another country. It is sold only with a doctor's prescription.[14]
  • Hong Kong: In Hong Kong, codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134, Schedule 1. It can be used legally only by health professionals and for university research purposes. The substance can be given by pharmacists under a prescription. However, codeine is available without prescription from licensed pharmacists in doses up to 0.1%[15]
  • Iceland: Preparations of paracetamol and codeine require a prescription in Iceland.[citation needed]
  • India: Codeine preparations require a prescription in India. Preparation of paracetamol and codeine is available in India. Codeine is also present in various cough syrups as codeine phosphate.[citation needed]
  • Iran: Preparations of codeine in Iran normally comes with paracetamol, but can be purchased over-the-counter. Iran's deputy health minister reported that codeine is Iran's best selling OTC medication. The recreational use of codeine has also become widespread throughout Iran but authorities continue to let codeine be purchased without permission from a doctor, although the pharmacist may ask for the identification of the purchaser to verify they are 18 years or older to buy.[citation needed]
  • Ireland: Codeine remains a semi non-prescriptive, over-the-counter drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public. Products containing more than 12.8 mg codeine are available on prescription only.[citation needed]
  • Italy: Codeine tablets or preparations require a prescription in Italy. Preparations of paracetamol and codeine are available in Italy as Co-Efferalgan and Tachidol.[citation needed]
  • Japan: Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics, antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC dispensing.[citation needed]
  • Maldives: The Maldives takes an infamously strict line on medicines, with many common drugs, anything containing codeine is banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned.[citation needed]
  • Romania: Codeine is not allowed without a medical prescription.[citation needed]
  • Russia: According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground desomorphine synthesis.[citation needed]
  • Spain: Codeine tablets or preparations require a prescription in Spain, although this is often not enforced and many pharmacies will sell codeine products without the requirement of a prescription.[citation needed]
  • Sri Lanka: Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of Codeine.[citation needed]
  • Sweden: Codeine is Schedule III under Swedish law, which means it is heavily regulated and sold only to those who have a prescription.[citation needed]
  • United Arabian Emirates: The UAE takes an exceptionally strict line on medicines, with many common drugs, notably anything with containing codeine being banned unless you have a notarized and authenticated doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or imprisoned. The US Embassy to the UAE maintains an unofficial list of what may not be imported.[citation needed]
  • United Kingdom: Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug when prepared for injection.[16] The possession of controlled substances without a prescription is a criminal offense.[17] However, certain preparations of codeine are exempt from this restriction under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc does not exceed 100 mg or 2.5% concentration in the case of liquid preparations.[citation needed]
  • United States: In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 90 mg per dosage unit. Tablets of codeine in combination with aspirin or acetaminophen (paracetamol/Tylenol) made for pain relief are listed as Schedule III; and cough syrups are Schedule III or V, depending on the formula.[citation needed]

See also

External links


  • Friswell J, Phillips C, Holding J, Morgan CJ, Brandner B, Curran HV. (2008). Acute effects of opioids on memory functions of healthy men and women. Psychopharmacology (Berl.). 198 (2): 243–50.
  • Schmidt, H., Vormfelde, S. V., Klinder, K., Gundert-Remy, U., Gleiter, C. H., Skopp, G., Aderjan, R. and Fuhr, U. (2002), Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors. Pharmacology & Toxicology, 91: 57–63.
  • Koch T, Höllt V. (2008). Role of receptor internalization in opioid tolerance and dependence. Pharmacol. Ther. 117 (2): 199–206.
  • Pert, C. B., Pasternak, G., & Snyder, S. H. (1973). Opiate Agonists and Antagonists Discriminated by Receptor Binding in Brain. Science, 182 (4119), 1359-1361.
  • Stefano GB, Ptáček R, Kuželová H, Kream RM. (2012). Endogenous morphine: up-to-date review (2011). Folia Biol. (Praha). 58 (2): 49–56. PMID 22578954.